JPS6058221B2 - Substituted diphenylamine and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a substituted diphenylamine, that is, 2,6-dichloro-4-nitrodiphenylamine (■
)02N NH■ (■) \ and its production.

The physical properties of this new compound, 2,6-dichloro-4nitrodiphenylamine (■), are as follows.

Boiling point 180-188℃/0.7Tr0nHg Melting point 112
~113℃C infrared absorption spectrum (Cm-1) 334013080, 1592, 1572, 1525,
150011455, 132 & 130 & 1140, 7 parts, 74 & 73 & tin 4, 4752●6-dichloro-4-nitrodiphenylamine (■) is a compound useful as an intermediate for O-(2,6-dichloroaniliephenylacetic acid (■)).

That is, the sodium salt of O-(2,6-dichloroanilinophenyl acetic acid (■)) is known as a drug having excellent pharmacological effects such as anti-inflammatory and analgesic effects under the common name ``diclofenac sodium''.

2,6-dichloro-4-nitrodiphenylamine (■) of the present invention
is reacted with oxalyl chloride using a catalyst such as aluminum chloride.
delCrafts) reaction to obtain 1-(2,6-dichloro-4-nitrophenyl)indoline-2,3-dione (V).

This 1-(2,6-dichloro-4-nitrophenyl)intrine-2,3-sion (■) is
amρ) reduction to form 1-4(4-amino-2,6-dichlorophenyl)-3-hydroxy-indolinone-2(■), and further reduction with hydroiodic acid and red phosphorus to form 1. -(4-amino-2●6-dichlorophenyl)indolinone (■). Alternatively, by directly reacting 1-(2,6-dichloro-4-nitrophenyl)indoline-2,3-dione (■) with hydroiodic acid and red phosphorus, 1-(4-amino-2 It is also possible to obtain 1-(4-amino-2,6-dichlorophenyl)indoline (■) without passing through phenyl)-3-hydroxy-indolinone-2 (■).

1-(4-amino-2,6-dichlorophenyl)indoline (■) is hydrolyzed with an alkali, for example sodium hydroxide, to produce O-(4-amino-2,6-dichloroaniline)phenylacetic acid (■). The sodium salt of Toshiko O-(4-amino-2,6-dichloroanilihaphenylacetic acid (■)) can be converted into a diazonium salt by reaction with an inorganic acid, such as hydrochloric acid, and an alkyl nitrite. , formalin-sodium hydroxide, and a reducing agent such as tetrahydrofuran to give 0-(2,6-dichloroanilino)phenylacetic acid.

2●6-dichloro-4-nitrodiphenylamine (■) of the present invention
The production process involves diazotizing the amino group of inexpensive 2,6-dichloro-4-nitroaniline (1), which is used industrially as an intermediate for azo disperse dyes as a raw material, and converting the diazonium salt to a halogen by Sandmeyer reaction, etc. 2●6-dichloro-4-
Nitrohalobenzene (■), as an example 2,6-dichloro-4-nitroiodobenzene (■-1).

Similarly, by reaction with copper bromide or copper chloride, 2●6-dichloro-4-nitroprombenzene (■-Br) or 1,2,3-trichloro-5-nitrobenzene (H-C
You can get more. This 2'6-dichloro-4-nitrohalobenzene (■) was added in excess, 5 to 20 moles of aniline and an alkali metal carbonate were added at a normal temperature of 150 to 20C). This is carried out by adding an inert solvent suitable for separation of reaction product water such as.

(However, X is a 1.Br.Cl group) In this reaction, the type of X has a considerable influence, and in the case of iodine, it tends to be much faster than that of chlorine.

Excess aniline and solvent from the reaction product were distilled off under reduced pressure.
The target compound and inorganic salts are extracted and separated using an aromatic hydrocarbon solvent and water, the aromatic hydrocarbon solution is concentrated under reduced pressure, and the mixture is distilled under reduced pressure and recrystallized using ethanol.
-dichloro-4-nitrodiphenylamine is obtained.

Next, in Examples, a method for producing 2,6-dichloro-4-nitrodiphenylamine and in a reference example, O
- Clarify a method for producing (2,6-dichloroanilino)phenylacetic acid.

The method for producing the substituted diphenylamine of the present invention and its related reactions are illustrated below. Example 1 (a) 2●6-dichloro-4-nitroyodobenzene (
■-■) Synthesis 200ml of concentrated sulfuric acid and 3 parts of sodium nitrite
8.5f(4). After adding 2,6-dichloro-4-nitroaniline (1) while keeping it at 0°C.
(Tokyo Kasei Products) A solution of 103.5y dissolved in 300mt of concentrated sulfuric acid.
Gradually add 200ml of concentrated phosphoric acid.

This reaction solution is poured into approximately 2k9 ice, filtered, and a solution of 100 y of potassium iodide and 300 mL of water is added to the solution in three parts.

After extraction with benzene and washing the benzene layer with an aqueous sodium thiosulfate solution, the benzene layer was concentrated to obtain 2●6-dichloro-4-nitroyodobenzene.

Yield: 91% The IR absorption peaks of the obtained compound are as follows.

152011505, 1367, 1333, 1160,
1111, 907, 883.80Cps75 & 733s
67\475(d-1) Physical property value Mpl5O~151sC
(b) 1,2,3-trichloro-5-nitrobenzene (
■-C1) Synthesis Almost the same as Example 1(a), concentrated sulfuric acid,
Sodium sulfite and 2,6-dichloro-4-nitroaniline (1) are reacted, and copper chloride is further reacted to form 1.
2,3-trichloro-5-nitrobenzene was obtained.

Yield: 79% The IR absorption (peak) of the obtained compound is as follows.

305011527, 1508, 1402, 1380,
1337, 1167, 1030, 902, 888, 81
0,76'3s73ku685,582 (Cm-1) Physical property value Mp69-709C Example 2 [2●6-dichloro-4-nitrodiphenylamine (■
) synthesis] 2●6-dichloro-4-nitroyodobenzene (■) 63.6y1 aniline 300y1 xylene 40
A mixture of 16 y of potassium carbonate and 16 y of potassium carbonate was maintained at 1700 C and refluxed for 5 hours while separating water produced by the reaction, and then 16 y of urium carbonate was added and refluxed for 5 hours.

After completion of the reaction, xylene and aniline were distilled off under reduced pressure, extracted with toluene and water, the toluene layer was concentrated, distilled under reduced pressure (180-188°C/0.7 wtHg), and further recrystallized with ethanol.

Yield 91% Physical properties Mpll2-113seC bp180-1881C/0.7Tf0nHg IR absorption peak (Cln-li is as follows.

3340, 308011592, 1572, 152\1
50011455, 132 & 130 people 1140179 &
74&73λB4, 475 Reference Example 1 [1-(2,6-dichloro-4-nitrophenyl)-indoline-2,3-
Synthesis of dione (■)] 2.6-dichloro-4-nitrodiphenylamine (■) 57y (0.2rn01e) was dissolved in oxalyl chloride 250y, and after reacting at room temperature for 2 days and further under reflux for 2 hours, under reduced pressure. Excess oxalyl chloride was distilled off to obtain a viscous liquid.

After adding 30 ml of tetrachloroethane and 50 y of aluminum chloride and reacting overnight at room temperature, the mixture was poured into ice water, extracted with 1000 ml of chloroform, the solvent was distilled off, and recrystallized with toluene. Compound obtained in 90% yield (
The (peak) of IR absorption of (2) is as follows.

310011757, 1737, 1612, 154 Snake 1
48, 1470, 1392, 1362, 1348, 13
05, 119011143, 1092, 885s842
, 81 74 λ 73 & 460
21rc Reference Example 2 [Synthesis of 1-(4-amino-2,6-dichlorophenyl)indolinone (■)] 1-(2,6-dichloro-4-
Nitrophenyl)-indoline-2,3-dione (■)
50y1 red phosphorus 90y157% hydroiodic acid 300mt
1 200ml of water and 300ml of xylene in a reflux state■
After reacting for an hour, hydroiodic acid and xylene were distilled off under reduced pressure to make the product alkaline and extracted with benzene.The extract was condensed and recrystallized with benzene.
◆6-Dichlorophenyno(c)indolinone (■) was obtained.

・Yield 92% The 1R absorption (peak) of this compound is as follows.

3450, 3330, 17001161\1600, 1
500, 1455, 1376, 1305, 1292, 1
248, 1198, 1178, 1076, 810175
01637, 557 (Cm-Rephysical properties Mp2O2~210
0C Reference Example 3 [Synthesis of 1-(4-amino-2,6-dichlorophenyl)indolinone (■)] 1-(2●6-dichloro-4-
Nitrophenyl) indoline-2,3-dione (■) 1
．． 7y1 iron powder 6 da, ethanol 30ml and water 10ml
0.2 ml of hydrochloric acid was added to the mixture, and the mixture was reacted under reflux for 4 hours.

When the product is hot) perform filtration? Concentrate the liquid and add 1-(4-
Amino-2,6-dichlorophenyl)-3-hydroxy-indolinone-2() was obtained. Yield Quantitative The main IR absorption peak (Cm-'') of this compound is as follows.

3450, 3360, 1725, 161ゝ1602, 1
502, 1468, 1180) 1062, 842, 81
752The 1-(4-amino2 ・6
-dichlorophenyl)-3-hydroxy-indolinone-20.5y) red phosphorus 1y) 57% hydroiodic acid 15
A mixture of ml and 4 mι of water was reacted for 1 hour at reflux temperature.

After the reaction is completed, hydroiodic acid is distilled off under reduced pressure, and the mixture is cooled.
Extracted with 5% sodium hydroxide and benzene, the benzene layer was filtered, washed with water, concentrated, and then extracted with acetone nihexane (1:
1) was subjected to chromatographic (TLC) separation to obtain 1-(4-amino-2,6-dichlorophenyl)indolinone ().

Yield: 80% The main IR absorption peak (Cm-'') of this compound is as follows.

3430, 3330, 1700, 161 anti-1600, 1
500, 1465, 1376, 1305, 1292, 1
248, 1198, 1178, 1076, 810, 75
0) 637, 557 Physical properties Mp2O3 ~ 210℃ Reference example 4 [-Na synthesis of 0-(4-amino-2,6-dichloroanilino)phenylacetic acid ()] 1-(4-amino-2.
6-dichlorophenyl)indolinone 1.0y (), sodium hydroxide 20y, water 100ml and ethanol 1
00 ml of the mixture was reacted at reflux for 4 hours.

The reaction product was concentrated as a methanol solution. Chromatographic (TLC) separation and 0-(4-amino-2,6
-Dichloroanilino)phenylacetic acid sodium salt was obtained.

The main IR absorption peaks (Cwt-”) of this compound are as follows: 337 to 292 to 1700, 161 & 1
602, 15 birds, 1500, 1482, 1382, 12
70, 1250, 1068, 837, 800, 74 & 6
08 Reference Example 5 Synthesis of 0-(2,6-dichloroanilino)phenylacetic acid () (a) 20 mι of tetrahydrofuran was added to 2.0 y of amyl sulfite and refluxed to produce 0-(4-amino-2,6-di Chloranilino)-phenylacetic acid sodium salt 1.
A solution of 00g and 50ml of tetrahydrofuran was added dropwise over 2 hours.

After the dropwise addition, reflux was continued for another 3 hours to stop the reaction.

The solvent and unreacted amyl nitrite were distilled off under reduced pressure, and the residue was dissolved in a mixture of 80 mt of water and 100 mι of ether.
Set the pH to 5.8.

Separate the ether layer. Furthermore, 0.3 y of sodium hydroxide dissolved in 80 mι of water was added to the ether layer, and the aqueous layer was separated. Further, the pH of the aqueous layer was adjusted to 5.8, and the precipitated solid was extracted with ether and concentrated to dryness. A 0.48f1 powder was obtained by fractionation using thin layer chromatography using methanol as a developing solvent. The IR) NMR and melting point of this product were consistent with those of 0-(2.6-dichloroanilino)phenylacetic acid synthesized by another method.

Yield 54% (b) Ethyl nitrite 4.0% instead of aluminum sulfite 2.09%.
A similar reaction treatment was performed using 0y to obtain a powder of 0.52y of 0-(2.6-dichloroanilino)phenylacetic acid.

Yield 58% Main IR of this compound obtained by methods (a) and (b) above
The absorption peak (Cm-'') is as follows.

Claims (1)

[Claims] 1. Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by (III). 2 Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, X represents a chlorine atom, a bromine atom, or an iodine atom.) A compound represented by the formula (II) and aniline are reacted to form the formula (I
II) A method for producing a substituted diphenylamine, which comprises obtaining a compound represented by (III).